PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion.
PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion.
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DOI：
10.1016/j.celrep.2017.05.092
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发表时间：
2017-06-27
期刊：
影响因子：
8.8
通讯作者：
Xu T
中科院分区：
文献类型：
--
作者：
Ma X;Lu JY;Dong Y;Li D;Malagon JN;Xu T
RAS基因在癌症中经常发生突变，但尚未开发出有效的治疗方法。这部分是由于对Ras相关肿瘤内信号传导的不完全理解。为了解决这个问题，我们在果蝇中进行了遗传筛选，旨在找到与致癌Ras（RasV12）合作诱导肿瘤过度生长和侵袭的突变。我们鉴定了蛋白磷酸酶6（PP6）复合物的调节亚基fierge mountain（fmt）作为肿瘤抑制因子，其与RasV12协同作用以驱动JNK依赖性肿瘤生长和侵袭。我们发现，Fmt负调控JNK上游的dTAK1。我们进一步证明，破坏PpV，PP6的催化亚基，模仿fmt功能丧失诱导的肿瘤发生。最后，Fmt与PpV协同抑制JNK依赖性肿瘤进展。我们的数据进一步强调了果蝇作为模型系统的力量，以揭示可能与人类癌症生物学相关的分子机制。
RAS genes are frequently mutated in cancers, yet an effective treatment has not been developed. This is partly due to an incomplete understanding of signaling within Ras-related tumors. To address this, we performed a genetic screen in Drosophila, aiming to find mutations that cooperate with oncogenic Ras (RasV12) to induce tumor overgrowth and invasion. We identified fiery mountain (fmt), a regulatory subunit of the protein phosphatase 6 (PP6) complex, as a tumor suppressor that synergizes with RasV12 to drive JNK-dependent tumor growth and invasiveness. We show that Fmt negatively regulates JNK upstream of dTAK1. We further demonstrate that disruption of PpV, the catalytic subunit of PP6, mimics fmt loss of function induced tumorigenesis. Finally, Fmt synergizes with PpV to inhibit JNK-dependent tumor progression. Our data here further highlight the power of Drosophila as a model system to unravel molecular mechanisms that may be relevant to human cancer biology.
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